In two, randomized, placebo-controlled, healthy volunteer
studies, Myrbetriq was associated with dose-related increases in supine blood
pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum
increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg
greater than placebo.

In contrast, in OAB patients in clinical trials, the mean
increase in systolic and diastolic blood pressure at the maximum recommended
dose of 50 mg was approximately 0.5 - 1 mmHg greater than placebo. Worsening of
preexisting hypertension was reported infrequently in Myrbetriq patients.

Urinary Retention in Patients with Bladder Outlet
Obstruction and in Patients Taking Antimuscarinic Medications for OAB

Urinary retention in patients with bladder outlet
obstruction (BOO) and in patients taking antimuscarinic medications for the
treatment of OAB has been reported in postmarketing experience in patients
taking mirabegron. A controlled clinical safety study in patients with BOO did
not demonstrate increased urinary retention in Myrbetriq patients; however,
Myrbetriq should be administered with caution to patients with clinically
significant BOO. Myrbetriq should also be administered with caution to patients
taking antimuscarinic medications for the treatment of OAB [see CLINICAL
PHARMACOLOGY].

Patients Taking Drugs Metabolized by CYP2D6

Since mirabegron is a moderate CYP2D6 inhibitor, the
systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is
increased when co-administered with mirabegron. Therefore, appropriate
monitoring and dose adjustment may be necessary, especially with narrow
therapeutic index drugs metabolized by CYP2D6, such as thioridazine,
flecainide, and propafenone [seeDRUG INTERACTIONS and CLINICAL
PHARMACOLOGY].

Patient Counseling Information

Inform patients that Myrbetriq
may increase blood pressure. Periodic blood pressure determinations are recommended,
especially in patients with hypertension. Myrbetriq has also been associated
with infrequent urinary tract infections, rapid heart beat, rash, and pruritis.
Inform patients that urinary retention has been reported when taking mirabegron
in combination with antimuscarinic drugs used in the treatment of overactive
bladder. Instruct patients to contact their physician if they experience these
effects while taking Myrbetriq.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Long-term carcinogenicity studies were conducted in rats
and mice dosed orally with mirabegron for two years. Male rats were dosed at 0,
12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at
0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at
systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher
in mice than the human systemic exposure at the 50 mg dose.

Mutagenesis

Mirabegron was not mutagenic in the Ames bacterial
reverse mutation assay, did not induce chromosomal aberrations in human
peripheral blood lymphocytes at concentrations that were not cytotoxic, and was
not clastogenic in the rat micronucleus assay.

Impairment of Fertility

Fertility studies in rats showed that mirabegron had no
effect on either male or female fertility at non-lethal doses up to 100
mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to
be 22 times the MRHD in women and 93 times the MRHD in men.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies using
Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if
the potential benefit to the patient outweighs the risk to the patient and
fetus. Women who become pregnant during Myrbetriq treatment are encouraged to
contact their physician.

Risk Summary

Based on animal data, mirabegron is predicted to have a
low probability of increasing the risk of adverse developmental outcomes above
background risk. Reversible adverse developmental findings consisting of
delayed ossification and wavy ribs in rats and decreased fetal body weights in
rabbits occurred at exposures greater than or equal to 22 and 14 times,
respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures
decreased fetal weights were observed in rats and rabbits, and fetal death,
dilated aorta, and cardiomegaly were reported in rabbits.

Animal Data

In the rat embryo/fetal developmental toxicity study,
pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300
mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of
gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96
times greater than exposures in women treated at the MRHD of 50 mg based on
AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the
human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or
greater than 22 times the human systemic exposure at the MRHD, delayed
ossification and wavy ribs were observed in fetuses at an increased incidence.
These findings were reversible.

In the rabbit embryo/fetal developmental toxicity study,
pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30
mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of
gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in
women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse
Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established
in this species based on reduced fetal body weight observed at systemic
exposures that were 14-fold higher than the human systemic exposure at MRHD. At
higher doses, where systemic exposures were 36-fold higher than the human
exposure at MRHD, maternal body weight gain and food consumption were reduced,
one of 17 pregnant rabbits died, the incidence of fetal death increased, and
fetal findings of dilated aorta and cardiomegaly were reported.

The effects of mirabegron on prenatal and postnatal
development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day
from the seventh day of gestation until 20 days after birth. Maternal systemic
exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on
AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation
had no discernable adverse effects at maternal systemic exposures 6 times the
MRHD. A slight but statistically significant decrease in the survival of pups
was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival)
compared to the control group (98.8%), however, there was no effect on survival
of pups 21 days after birth. Absolute body weight of pups was not affected on
the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic
exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13%
from postnatal day 4 to 7 but not throughout the remainder of the lactation
period. In utero and lactational exposure did not affect behavior or fertility
of offspring at exposures up to 22 times the MRHD.

Nursing Mothers

It is not known whether Myrbetriq is excreted in human
milk. Mirabegron was found in the milk of rats atconcentrations twice the
maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of
nursing pups. No studies have been conducted to assess the impact of Myrbetriq
on milk production in humans, its presence in human breast milk, or its effects
on the breast-fed child. Because Myrbetriq is predicted to be excreted in human
milk and because of the potential for serious adverse reactions in nursing
infants, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.

Pediatric Use

The safety and effectiveness of Myrbetriq in pediatric
patients have not been established.

Geriatric Use

No dose adjustment is necessary for the elderly. The
pharmacokinetics of Myrbetriq is not significantly influenced by age [see CLINICAL
PHARMACOLOGY]. Of 5648 patients who received Myrbetriq in the phase 2 and 3
studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75
years of age or older. No overall differences in safety or effectiveness were
observed between patients younger than 65 years of age and those 65 years of
age or older in these studies.

Renal Impairment

Myrbetriq has not been studied in patients with end stage
renal disease (CLcr < 15 mL/min or eGFR < 15 mL/min/1.73 m² or patients
requiring hemodialysis), and, therefore is not recommended for use in these patient
populations.

In patients with severe renal impairment (CLcr 15 to 29
mL/min or eGFR 15 to 29 mL/min/1.73 m²), the daily dose of Myrbetriq should not
exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate
renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m²) [see CLINICAL
PHARMACOLOGY].

Hepatic Impairment

Myrbetriq has not been studied in patients with severe
hepatic impairment (Child-Pugh Class C), and therefore is not recommended for
use in this patient population.